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Daratumumab and Hyaluronidase-fihj for the Treatment of Polyneuropathy Associated with MGUS
Trial Status: active
This phase II trial studies how well daratumumab and hyaluronidase-fihj works in treating patients with damage to nerves (polyneuropathy) that is being caused by an immune disorder known as monoclonal gammopathy of undetermined significance (MGUS). MGUS causes an abnormal protein to be found in the blood. This protein is a monoclonal protein or M protein, and is formed within the bone marrow, the soft, blood-producing tissue that fills in the center of most of the bones. The disorder typically does not cause any problems, however in a small proportion of people, the proteins can cause organ problems or nerve problems. Rarely, MGUS can transform into a cancer. Daratumumab is a monoclonal antibody that targets CD-38 (a protein found on the surface of plasma cells) and causes destruction of the abnormal cell, and hyaluronidase, which is a class of protein called endoglycosidase (an enzyme). The hyaluronidase allows daratumumab to be given by an injection under the skin. Daratumumab and hyaluronidase-fihj may be able to stop the bone marrow from making the M protein and causing further damage to nerves.
Inclusion Criteria
Age ≥ 18 years at the time of informed consent
A diagnosis of polyneuropathy based on clinical assessment of a neurologist, with chronic inflammatory demyelinating polyneuropathy (CIDP) diagnosis made according to the European Federation of Neurological Societies/Peripheral Nerve Society guidelines with concurrent diagnosis of monoclonal gammopathy of undetermined significance (MGUS) with an immunoglobulin M (IgM) monoclonal peak
EMG/NCS consistent with polyneuropathy. Patients are allowed to have been exposed to prior treatments, including corticosteroids, intravenous or subcutaneous immunoglobulin treatment or rituximab. No wash out period is required. Participants who received treatment for their neuropathy within 6 months before study entry or who discontinued treatment are required to have evidence of clinically meaningful symptoms per INCAT score
Patients will have to have disability associated with their peripheral neuropathy, with a baseline INCAT Sensory Score (ISS) score ≥ 4
Must meet MGUS diagnostic criteria as diagnosed using International myeloma Working Group (IMWG) criteria using the following criteria
* Serum monoclonal protein < 30g/L
* Clonal bone marrow lymphoplasmacytic/plasma cells < 10%
* Absence of end-organ damage related to the plasma cell dyscrasia
** If patient has end organ damage that is felt to not be secondary to underlying plasma cell dyscrasia, accompanying justification by investigator/clinician required
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 3
Total white blood cell (WBC) count ≥ 1,500/mm^3, absolute neutrophil count (ANC) ≥ 1,000/mm^3
Hemoglobin (Hb) ≥ 8.0 g/dL
Platelet count ≥ 75,000/mm^3
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN)
Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 2.5 is permissible if due to disease
Bilirubin ≤ 2 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin for which > 2 x ULN is an acceptable limit)
Creatinine clearance ≥ 20mL/min
Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥ 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for at least 3 months after the last dose of study drug
Exclusion Criteria
Documented active multiple myeloma, smoldering myeloma, Waldenström's macroglobulinemia, non-IgM MGUS, plasma cell leukemia or systemic amyloid light chain amyloidosis
Concomitant disorder felt to possibly be related to the etiology of the peripheral neuropathy: diabetes, vitamin deficiency, chronic alcohol consumption, drugs, HCV infection
* To rule out alternative causes of peripheral neuropathy, patients must have had a peripheral neuropathy workup (by a neurologist). A clinical history should evaluate the time course and evolution of the neuropathy, family history, pain, fever, nights sweats, weight loss, exposures to neurotoxic medications (especially prior chemotherapies), alcohol use (current and past), vitamin deficiencies, HCG/HIV infections, as well as diabetes. Additionally, there should be a neurological examination evaluating the type of nerve fibre involvement and distribution. This can include evaluations with physical exam, laboratory exams, EMG/NCS or nerve biopsies
Prior or current exposure to any of the following:
* To daratumumab and hyaluronidase-fhj or other anti-CD-38 therapies (unless a re-treatment study)
* Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer
Serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11mg/dL)
Bone lesions: One or more osteolytic lesion on skeletal radiography, CT, or PET/CT
Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having chronic obstructive pulmonary disease (COPD) and participants must be excluded if forced expiratory volume in 1 second (FEV1) is < 50% of predicted normal
Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate
Participant is:
* Known history of human immunodeficiency virus (HIV)
* Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screed using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (hepatitis B surface antibody [anti-HBs] positivity as the only serologic marker) AND a known history of HBV vaccination, do not need to be testing for HBV DNA by PCR
* Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
Patients who have implanted deep brain stimulators and vagal nerve stimulators
Clinically significant cardiac disease, including:
* Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
* Uncontrolled cardiac arrhythmia
* Patients with external pacing wires or intracardiac catheters
If patient is unable to sign informed consent due to any serious medical condition, laboratory abnormality or psychiatric illness
If patient is pregnant or breastfeeding, a prisoner, or not yet an adult
Any life-threatening illness, medical condition, concomitant active cancer, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
Additional locations may be listed on ClinicalTrials.gov for NCT06046287.
I. To assess the efficacy of daratumumab and recombinant human hyaluronidase (daratumumab and hyaluronidase-fihj) in MGUS patients, as determined by absolute changes from baseline in functional assessment inflammatory neuropathy cause and treatment (INCAT) sensory (ISS) score.
SECONDARY OBJECTIVES:
I. To assess efficacy by absolute changes in other functional assessments (clinical examination, and nerve conduction velocity studies [NCS]/electromyography [EMG] measures) and by improvement in health-related quality of life measures (the modified Rankin Score, INCAT disability scale, and 36-item Short Form Health Survey [SF-36] score) with treatment of daratumumab and hyaluronidase-fihj.
II. To assess if there is an improvement in MGUS laboratory studies with treatment.
OUTLINE:
Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1-2 and on days 1 and 15 of cycles 3-6. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo EMG, NCS, and blood sample collection throughout the trial.
After completion of study treatment, patients are followed up at 9 and 12 months.
Trial PhasePhase II
Trial Typesupportive care
Lead OrganizationMedStar Georgetown University Hospital
